Patients treated with pirfenidone in the ASCEND and CAPACITY trials had a 48% reduction in the mortality hazard at 1 year compared with placebo-treated patients (95% CI 0.31-0.87, P=0.011). A meta-analysis of the two trials confirmed the significant reduction in all-cause mortality.

The results mirrored those of the individual trials, which demonstrated similar reductions in the mortality hazard but lacked statistical power to achieve statistical significance, Steven Nathan, MD, of Inova Fairfax Hospital in Falls Church, Va., reported here at CHEST 2015.

"Both pooled and meta-analyses of data from the ASCEND and CAPACITY trials consistently favored pirfenidone in reducing the risk of all-cause mortality in patients with IPF," said Nathan. "The near-identical results of the pooled and meta-analyses for all-cause mortality highlight the robustness of pooling data for evaluating other efficacy outcomes of pirfenidone. These findings provide additional evidence to support the use of pirfenidone in patients with IPF."

The results confirm and extend the individual trials' data, which showed significant improvement in the primary endpoint related to lung function trends toward a reduction in all-cause mortality, said discussion moderator Tejaswini Kulkarni, MD, of the University of Alabama at Birmingham.

"We could see a trend toward a lower all-cause mortality in each of the trials," Kulkarni told MedPage Today. "The pooled data provided the added statistical power to see a significant reduction in all-cause mortality, and this was confirmed by the meta-analysis. The new analyses give us added confidence and justification for using pirfenidone in patients with IPF."

The FDA approved pirfenidone for IPF in October 2014, following the agency's granting of priority review, fast track, orphan drug, and breakthrough status for the drug. Data to support the approval came from multiple randomized trials, which consistently showed that patients treated with pirfenidone had improved lung function versus comparators, the trials' primary endpoint. All-cause mortality was a secondary endpoint, and each of the trials demonstrated a trend toward lower mortality but not a significant benefit.

All-cause mortality has been proposed as a standard endpoint for clinical trials in IPF, said Nathan. However, clinical trials in IPF typically have a low mortality, increasing the difficulty of demonstrating a statistically significant benefit.

Data pooling and meta-analyses offer viable options for increasing the statistical power to evaluate clinical endpoints, particularly mortality, Nathan continued. Toward that end, investigators in two large randomized trials of pirfenidone in IPF analyzed pooled data and performed a meta-analysis of pooled data for the secondary endpoint of all-cause mortality.

Investigators in CAPACITY clinical program performed two phase III randomized, placebo-controlled trials involving a total of 779 patients. Treatment continued for a minimum of 72 weeks, and follow-up continued until the trials were closed. The phase III, randomized ASCEND trial involved 555 patients who were followed for 52 weeks.

All-cause mortality was defined as death from any cause at any time during the study. Investigators employed the DerSimonian and Laird (random effects) methodology of meta-analysis. In the three trials combined, 44 pirfenidone-treated patients died during follow-up and 58 deaths occurred among placebo-treated patients.

Trial results showed substantial reductions in the hazard for all-cause mortality in all three trials, but none of the differences achieved statistical significance. In contrast, results at 52 weeks were statistically significant by pooled data and meta-analysis:

CAPACITY-1: HR 0.67, 95% CI 95% CI 0.24-1.87

CAPACITY-2: HR 0.37, 95% CI 0.13-1.04

ASCEND: HR 0.55, 95% CI 0.26-1.15

Pooled data: HR 0.52, 95% CI 0.21-0.87, P-0.0107

Meta-analysis: HR 0.52, 95% CI 0.21-0.88, P=0.0138

The pooled analysis of 72-week data yielded a hazard ratio of 0.63 (95% 0.41-0.98, P=0.0404), and the meta-analysis resulted in a hazard ratio of 0.64 (95% CI 0.41-0.99, P=0.0485).

The analyses of follow-up to end of study or week 120 showed trends in favor of pirfenidone in each of the three individual trials (HR 0.95 to HR 0.55), none of which achieved statistical significance. The pooled analysis yielded a nonsignificant 31% reduction in the hazard for all-cause mortality (HR 0.69, 95% CI 0.44-1.05), as did the meta-analysis (HR 0.69, 95% CI 0.46-1.06).

The CAPACITY trials were supported by InterMune and the ASCEND trial by Genentech.

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